A Transannular Polyene Tetracyclization for Rapid Construction of the Pimarane Framework

Abstract Polyene cyclizations are one of the most powerful and fascinating chemical transformations to rapidly generate molecular complexity. However, cyclizations employing heteroatom‐substituted polyenes are rare. Described here is the tetracyclization of a dual nucleophilic aryl enol ether involving an unprecedented transannular endo‐termination step. In this transformation, five stereocenters, two of which are quaternary, four carbon–carbon bonds, and four six‐membered rings are formed from a readily available cyclization precursor. The realization of this cyclization enabled short synthetic access to the tricyclic diterpenoid pimara‐15‐en‐3α‐8α‐diol.

A Transannular Polyene Tetracyclization for the Rapid Construction of the Pimarane Framework -Supporting Information

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Optical rotation values were recorded on a Schmidt+Haensch UniPol L1000 Peltier polarimeter. The specific rotation is calculated as follows: [ ] = ∝ × 100 × . Thereby, the wavelength λ is reported in nm and the measuring temperature in °C. α represents the recorded optical rotation, c the concentration of the analyte in 10 mg/mL and d the length of the cuvette in dm. Thus, the specific rotation is given in 10 −1 ·deg·cm 2 g −1 . Use of the sodium D line (λ = 589 nm) is indicated by D instead of the wavelength in nm. The sample concentration as well as the solvent is reported in the relevant section of the experimental part.
X-Ray diffraction analysis was carried out by Dr. Klaus Wurst at the Institute of Inorganic and Theoretical Chemistry and Center for Molecular Biosciences, University of Innsbruck. The data collections were performed on a Bruker D8 Quest diffractometer (Photon 100 detector) equipped with a microfocus source generator (Incoatec GmbH, Geesthacht, Germany) combined with multi-layer optics (monochromatized Mo Kα radiation, λ = 71.073 pm). The Bruker Apex III software was applied for the integration, scaling and multi-scan absorption correction of the data. The structure was solved with SHELXS [1] (version 2013/1). Structure refinement (full-matrix least-squares against F²) with SHELXL [2] (version 2014/7). All nonhydrogen atoms were refined anisotropically. The hydrogen atoms were placed in ideal geometry riding on their parent atoms. Relevant details of the data collection and evaluation are listed in chapter 5. Supplementary crystallographic data for 8a, 8b, 19 and 25 may be obtained from the Cambridge Crystallographic Data Centre CCDC deposition service via www.ccdc.cam.ac.uk/structures on quoting the deposition number CCDC 1987621-1987624. Plotting of thermal ellipsoids in this document and in the main text was carried out using MERCURY for Windows at 50% probability level.
All yields are isolated, unless otherwise specified.
To a solution of the impure fraction of 8c (12.8 mg, assuming 33.3 µmol, 1 equiv) in pyridine (890 µl) was sequentially added N,N-dimethylpyridin-4-amine (6.1 mg, 50 µmol, 1.5 equiv) and benzoyl chloride (7.7 µl, 67 µmol, 2.0 equiv) at 22 °C. After 29 h, the reaction mixture was concentrated, and the residue dissolved in ethyl acetate (10 mL To a suspension of iron(III) chloride (84.4 mg, 520 µmol, 2.00 equiv) in dry dichloromethane (17 mL), cyclization precursor 9 (100 mg, 260 µmol, 1 equiv) in dry dichloromethane (17 mL) was added over 120 sec at -50 °C. The reaction mixture was slowly warmed to -20 °C over 2 h within the Dewar vessel by switching off the electronically regulated cryostat. Triethylamine (162 µl, 1.17 mmol, 4.50 equiv) was added to the orange suspension leading to a color change to yellow. The reaction mixture was poured into 1 M aqueous solution of sodium hydroxide (34 mL). The aqueous layer was extracted with dichloromethane (4 x 50 mL), and the combined organic layers were dried over magnesium sulfate. The dried solution was filtered, and the filtrate was concentrated. Purification of the residue by flash column chromatography on silica gel (10% ethyl acetate in pentane) yielded a mixture of tetracyclization products 8a, 8b, 8c and 8d along with other impurities. From the mixture the desired isomers 8a and 8b were separated by preparative normal-phase HPLC (1.0% grading to 2.0% i-propanol in n-hexane over 120 min) to yield 8a (12.5 mg, 32.5 µmol, 13%) as a colorless foam, 8b (13.1 mg, 34.1 µmol, 13%) as a colorless solid, a mixture of 8c with other impurities (14.8 mg) and a mixture of 8d with other impurities (18.6 mg).

Large-Scale cyclization:
To a solution of cyclization precursor 9 (742 mg, 1.93 mmol, 1 equiv) in dry dichloromethane (276 mL) in a 1-L round bottom flask equipped with a 40-mm olive-shaped magnetic stirring A Transannular Polyene Tetracyclization for the Rapid Construction of the Pimarane Framework -Supporting Information S16 bar was added SnCl4 (100 mM in dichloromethane, 28.9 mL, 2.89 mmol, 1.50 equiv) via syringe pump (60 mL/ h) at -78 °C under vigorous stirring (600 rpm). After the addition was complete, the solution was stirred for 20 min before triethylamine (1.20 mL, 8.68 mmol, 4.50 equiv) was added dropwise to the orange solution leading to decolorization. The reaction mixture was poured into 1 M aqueous solution of sodium hydroxide (280 mL). The aqueous layer was extracted with dichloromethane (2 x 400 mL) and the combined organic layers were dried over magnesium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (3% grading to 7.5% ethyl acetate in pentane) yielding a mixture of tetracyclization products 8a, 8b, 8c and 8d along with other impurities. From the mixture the desired isomers 8a and 8b were isolated by preparative normal-phase HPLC (1.0% grading to 2.0% i-propanol in n-hexane over 120 min) yielding 8a (139 mg, 85% purity by NMR, 305 µmol, 16%) as mixture with other diastereomers, which could be further purified by recrystallisation from refluxing acetonitrile (1 mL) to give clean pentacyclic product 8a (86.0 mg, 224 µmol, 12%). The regioisomer 8b was obtained as a mixture with other impurities (92.2 mg), which was used for the next step, after which the impurities could be removed by flash column chromatography on silica gel.

Epoxide fragment S8
To a solution of diol S7 (1.60 g, 3.87 mmol, 1 equiv) and pyridine (1.56 mL, 19.4 mmol, 5.00 equiv) in dry dichloromethane (16 mL) was added methanesulfonyl chloride 10 (449 µl, 5.8 mmol, 1.50 equiv) at 0 °C. The cooling bath was removed, and the reaction mixture was allowed to warm to 22 °C. After 19 h, water (40 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 40 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated. To the residue was added benzene (15 mL) and solution was concentrated.
The residue (assuming 1.90 g, 3.87 mmol, 1 equiv) was dissolved in dry methanol (50 mL) before potassium carbonate (1.07 g, 7.74 mmol, 2.00 equiv) was added. 11 After 2 h, water (50 mL) was added and the aqueous layer was extracted with dichloromethane (100 mL, then 2 x 50 mL). The combined organic layers were washed with saturated aqueous solution of sodium chloride (50 mL), the washed solution was dried over magnesium sulfate, the dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (5% grading to 7.5% ethyl acetate in pentane) yielding epoxide S8 (1.16 g, 2.94 mmol, 76% over 2 steps) as a colorless oil. To a solution of iodide 18 (74.4 mg, 379 µmol, 1.50 equiv) and 9-methoxy-9borabicyclo[3.3.1]nonane (1.00 M in hexanes, 885 µl, 885 µmol, 3.50 equiv) in degassed dry tetrahydrofuran (1.5 mL) was added tert-butyllithium (1.84 M in pentane, 619 µL, 1.14 mmol, 4.50 equiv) dropwise at −78 °C. The solution turned yellow and then colorless. After 5 min, the cooling bath was replaced by a water bath (22 °C) and the mixture was warmed to 22 °C. After 5 min, the reaction mixture was cooled to −78 °C. A degassed 9:1 mixture of dimethylformamide and water (100 µl) was added to the clear solution and the cooling bath was removed. The reaction mixture was allowed to warm to 22 °C.
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Epoxide fragment S13 To a solution of diol S12 (408 mg, 920 µmol, 1 equiv) and pyridine (371 µL, 4.60 mmol, 5.00 equiv) in dry dichloromethane (4.0 mL) was added methanesulfonyl chloride 14 (107 µl, 1.38 mmol, 1.50 equiv) at 0 °C. The cooling bath was removed and the reaction mixture was allowed to warm to 22 °C. After 23 h, water (4.0 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 4 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated. To the residue was added benzene (15 mL) and the solution was concentrated.
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Epoxide fragment S18 To a solution of diol S17 (171 mg, 386 µmol, 1 equiv) and pyridine (155 µL, 1.93 mmol, 5.00 equiv) in dry dichloromethane (1.7 mL) was added methanesulfonyl chloride 18 (45.1 µl, 579 µmol, 1.50 equiv) at 0 °C. The cooling bath was removed, and the reaction mixture was allowed to warm to 22 °C. After 17 h, water (2 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 4 mL). The combined organic layers were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated. To the residue was added benzene (15 mL) and the solution was concentrated.
The residue (assuming 201 mg, 386 µmol, 1 equiv) was dissolved in dry methanol (3.9 mL) before potassium carbonate (107 mg, 771 µmol, 2.00 equiv) was added. 19 After 1.5 h, water (5 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, the dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (5% ethyl acetate in cyclohexane) yielding epoxide S18 (100 mg, 235 µmol, 61% over 2 steps) as a colorless oil. Cyclization precursor S19 To a solution of iodide 18 (34.6 mg, 176 µmol, 1.50 equiv) and 9-methoxy-9borabicyclo[3.3.1]nonane (1.00 M in hexanes, 411 µl, 411 µmol, 3.50 equiv) in degassed dry tetrahydrofuran (718 µL) was added tert-butyllithium (1.84 M in pentane, 287 µL, 529 µmol, 4.50 equiv) dropwise at −78 °C. The solution turned yellow and then colorless. After 5 min, the cooling bath was replaced by a water bath (22 °C) and the reaction mixture was warmed to 22 °C. After 5 min the reaction mixture was cooled to −78 °C. A degassed 9:1 mixture of dimethylformamide and water (50 µl) was added to the clear solution and the cooling bath was removed. The reaction mixture was allowed to warm to 22 °C.
To a solution of iodide 18 (80.5 mg, 411 µmol, 1.50 equiv) and 9-methoxy-9borabicyclo[3.3.1]nonane (1.00 M in hexanes, 958 µL, 958 µmol, 3.50 equiv) in degassed dry tetrahydrofuran (1.7 mL) was added tert-butyllithium (1.60 M in pentane, 770 µL, 1.23 mmol, 4.50 equiv) dropwise at −78 °C. The solution turned yellow and then colorless. After 30 min, the cooling bath was replaced by a water bath (22 °C) and the mixture was warmed to 22 °C. After 5 min the mixture was cooled to -78 °C. A degassed 9:1 mixture of dimethylformamide and water (1 mL) was added to the clear solution and the cooling bath was removed. The reaction mixture was allowed to warm to 22 °C.
To a solution of enol ether (Z)-S25 (20.0 mg, 54.3 µmol, 1 equiv) in dry dichloromethane (7.8 mL) was added SnCl4 (100 mM in dichloromethane, 814 µL, 81.4 µmol, 1.50 equiv) dropwise over 48 sec at -78 °C. After 20 min, triethylamine (33.8 µl, 244 µmol, 4.50 equiv) was added to the yellow solution leading to decolorization and the reaction mixture was poured into 2 M aqueous solution of sodium hydroxide (7 mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL), and the combined organic layers were dried over magnesium sulfate. The dried solution was filtered, and the filtrate was concentrated. 1 H NMR analysis of the residue revealed (Z)-S25 as the major component (75% NMR purity) along with decomposition products:

NMR comparison data for pimara-15-en-3α-8α-diol (7)
* The signal overlapped with at least one other signal, but the chemical shift could be assigned via the HSQC spectrum.